CN109651282A - A kind of synthesis four replaces the new method of connection alkene - Google Patents
A kind of synthesis four replaces the new method of connection alkene Download PDFInfo
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- CN109651282A CN109651282A CN201811558487.XA CN201811558487A CN109651282A CN 109651282 A CN109651282 A CN 109651282A CN 201811558487 A CN201811558487 A CN 201811558487A CN 109651282 A CN109651282 A CN 109651282A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
It is, using propyne derivative and azlactone as reaction raw materials, using chiral phosphoric acid as catalyst, to react to obtain four substitution connection vinyl compounds in reaction dissolvent the invention discloses the synthetic method that one kind four replaces connection vinyl compound.Reaction condition of the present invention is mild, and raw material is easy to get inexpensive, and operation is simple, and yield is higher, provides crucial skeleton structure for the synthesis of many natural products and drug, can be widely used in industrial-scale production.
Description
Technical field
Present invention relates particularly to a kind of synthetic methods for preparing four substitutions connection vinyl compound, belong to organic compound technique
Applied technical field.
Background technique
Four replace connection vinyl compound to be a kind of extremely important pharmaceutical-chemical intermediate, have very high application value.
Four replace connection alkene to be alternatively arranged as chiral complex, chiral catalyst etc..It is as follows:
Four replace the conventional method of connection alkene mainly by using the spontaneous preparation that is converted of metal catalytic or chiral alkynes.But
It is that the use of the at high cost and heavy metal of spontaneous conversion can cause environment seriously to pollute, the application of the method is made to be restricted.
Summary of the invention
The present invention overcomes the disadvantages described above of the prior art, innovatively proposes for the first time a kind of environmentally protective, is simple and efficient system
Standby four replace the new method of connection vinyl compound, are catalyst by using chiral phosphoric acid, can efficiently realize turning for reaction
Change.As shown in the above formula (I), it is catalysis with chiral phosphoric acid that the present invention, which is utilized using propyne derivative and azlactone as reaction raw materials,
Agent is reacted in reaction dissolvent, and synthesis four replaces connection vinyl compound.
In the present invention, R is alkyl or aromatic radical or substituted aromatic ring and heterocycle, all kinds of side chains.
In the present invention, the usage ratio of the starting material propyne derivative and azlactone is 1:1-1:5.Preferably, two
Person's usage ratio is 1:1.2.
In the present invention, the catalyst is chiral phosphoric acid；The dosage of the catalyst is 1-100%.The catalyst
Dosage is the 1-100mol% of raw material propyne derivative.Preferably, the catalyst amount is 1mol%.
In the present invention, the reaction dissolvent be methylene chloride, chloroform, tetrahydrofuran, methanol, 1,2- dichloroethanes,
Acetonitrile, toluene, 1,4- dioxane.The reaction dissolvent include but is not limited to more than, can also be ether, ethyl acetate,
Benzotrifluoride, xylene compound or methyl phenyl ethers anisole.
In the present invention, the synthetic reaction is carried out at a temperature of 0-80 DEG C.It preferably, is carried out anti-at a temperature of 25 DEG C
It answers.
Specifically, synthetic reaction of the present invention is in reaction flask A, by propyne derivative (substrate 1, X mmol) and azlactone
(substrate 2, Y mmol) is dissolved in Z mL reaction dissolvent, at room temperature, is added chiral phosphoric acid (W mmol).Reaction is at 0-80 DEG C
React 48 hours.Reaction process is detected with TLC.After completion of the reaction, directly plus silica gel, dry chromatography, isolated target are revolved
Product 3.
The advantages of synthetic reaction of the present invention includes: that each raw material used in synthetic method of the present invention is very simple, is work
Industry commodity, it is simple and easy to get, it is from a wealth of sources, and performance is highly stable, does not need special preservation condition.It is each used in the present invention
Kind catalyst is also all common commercial reagents, highly stable.Synthesis four replaces traditional method one of connection vinyl compound
As be to be realized using reacting for the propyne derivative of metal catalytic and other substrates.But due to the adaptation of propyne derivative
Property is not extensive enough, and the use of heavy metal can cause environment seriously to pollute, and very big limitation is caused to industrialized production.The present invention
Using propyne derivative and azlactone simple and easy to get as reaction raw materials, under chiral phosphoric acid effect, reaction obtains four substitutions connection alkene
Class compound.Operation is fairly simple, and reaction condition is mild, and yield is higher, is suitble to large-scale industrial production.The present invention closes
At four replace connection vinyl compounds be many natural products and active drug molecule core skeleton, innovative design of the present invention
Reaction route provides a generally applicable preparation method to synthesize this kind of compound.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail, and of the invention protects content not limit to
In following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that variation and excellent
Point is all included in the present invention, and using appended claims as protection scope.Implement process of the invention, condition,
Reagent, experimental method etc. are among the general principles and common general knowledge in the art, this hair in addition to what is specifically mentioned below
It is bright that there are no special restrictions to content.Data given by following embodiment include concrete operations and reaction condition and product.Product is pure
Degree is identified by nuclear magnetic resonance.
Embodiment 1
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2a (0.06mmol, 13.1mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3aa (93%).1H NMR(CDCl3,500MHz):δ(ppm)7.95-7.93(m,2H),7.50-
7.45(m,4H),7.37-7.27(m,7H),7.25-7.22(m,1H),6.96-6.95(m,2H),6.80-6.79(m,2H),
6.62 (s, 1H), 3.84 (s, 3H), 2.30 (q, J=10.0Hz, 2H), 0.91 (t, J=10.0Hz, 3H)13C NMR(CDCl3,
125MHz):δ(ppm)205.5,178.5,163.2,160.8,155.6,136.0,134.5,129.9,129.7,128.7,
128.6,128.5,128.3,127.7,127.7,117.9,115.5,114.2,113.5,110.0,108.8,76.1,55.5,
29.5,8.2.HRMS(ESI):exact mass calculated for M+(C33H28NO4)requires m/z
502.2018,found m/z 502.2014.
Embodiment 2
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2b (0.06mmol, 11.3mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ab (75%).1H NMR(DMSO-d6,500MHz):δ(ppm)9.66(s,1H),7.94-7.93
(m,2H),7.67-7.64(m,1H),7.57-7.53(m,2H),7.43-7.40(m,4H),7.36-7.30(m,5H),7.25-
7.24 (m, 1H), 7.11-7.10 (m, 2H), 6.76-6.74 (m, 2H), 2.12 (q, J=10.0Hz, 2H), 0.77 (t, J=
10.0Hz,3H).13C NMR(DMSO-d6,125MHz):δ(ppm)205.3,178.1,160.7,157.9,135.8,134.4,
133.8,129.7,129.4,129.2,129.1,128.5,128.4,128.1,125.3,116.1,113.7,108.4,76.1,
29.2,8.3.HRMS(ESI):exact mass calculated for M+(C32H26NO3)requires m/z
472.1913,found m/z 472.1913.
Embodiment 3
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2c (0.06mmol, 12.4mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ac (65%).1H NMR(CDCl3,500MHz):δ(ppm)7.99-7.96(m,2H),7.48-
7.46(m,2H),7.43-7.42(m,2H),7.38-7.27(m,6H),7.25-7.23(m,2H),7.16-7.13(m,2H),
6.79-6.78 (m, 2H), 5.31 (s, 1H), 2.25 (q, J=10.0Hz, 2H), 0.87 (t, J=10.0Hz, 3H)13C NMR
(CDCl3, 125MHz): δ (ppm) 205.5,178.1,165.5 (d, J=1010.0Hz), 160.1,155.4,135.9,
(134.3,130.5,130.4,129.7,128.7,128.6,128.5,128.4,127.8 d, J=30.0Hz), 121.9 (d, J
=10.0Hz), 116.1 (d, J=90.0Hz), 115.5,113.6,108.5,76.4,29.4,8.2.HRMS (ESI): exact
mass calculated for M+(C32H25FNO3)requires m/z 490.1740,found m/z 490.1743.
Embodiment 4
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2d (0.06mmol, 13.4mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ad (70%).1H NMR(CDCl3,500MHz):δ(ppm)7.92-7.90(m,2H),7.49-
7.43(m,6H),7.38-7.27(m,7H),7.24-7.23(m,1H),6.80-6.78(m,2H),5.77(s,1H),2.28(q,
J=10.0Hz, 2H), 0.88 (t, J=10.0Hz, 3H)13C NMR(CDCl3,125MHz):δ(ppm)205.5,178.0,
160.2,155.5,139.2,135.8,134.3,129.7,129.3,129.2,128.6,128.6,128.5,128.4,
127.8,127.8,127.7,124.1,115.5,113.7,108.5,76.4,29.4,8.2.HRMS(ESI):exact mass
calculated for M+(C32H25ClNO3)requires m/z 506.1523,found m/z 506.1523.
Embodiment 5
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2e (0.06mmol, 12.2mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ae (93%).1H NMR(CDCl3,500MHz):δ(ppm)7.88-7.86(m,2H),7.49-
7.44(m,4H),7.37-7.27(m,8H),7.24-7.21(m,2H),6.80-6.78(m,2H),6.12(s,1H),2.41(s,
3H), 2.29 (q, J=10.0Hz, 2H), 0.89 (t, J=10.0Hz, 3H)13C NMR(CDCl3,125MHz):δ(ppm)
205.5,178.4,161.1,155.4,143.6,136.0,134.4,129.7,129.5,128.7,128.6,128.5,
128.3,128.0,127.8,127.7,127.7,122.8,115.5,113.5,108.7,76.2,29.5,21.7,8.2.HRMS
(ESI):exact mass calculated for M+(C33H28NO3)requires m/z 486.1991,found m/z
486.1997.
Embodiment 6
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2f (0.06mmol, 13.4mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3af (94%).1H NMR(CDCl3,500MHz):δ(ppm)8.00(s,1H),7.86-7.84
(m,1H),7.53-7.50(m,3H),7.47-7.46(m,2H),7.40-7.37(m,3H),7.34-7.27(m,6H),6.81-
6.80 (m, 2H), 6.08 (s, 1H), 2.31 (q, J=10.0Hz, 2H), 0.90 (t, J=10.0Hz, 3H)13C NMR(CDCl3,
125MHz):δ(ppm)205.5,177.8,159.9,155.4,135.8,135.0,134.2,132.8,130.1,129.7,
128.6,128.6,128.5,128.4,128.0,127.9,127.8,127.7,127.4,126.1,115.5,113.7,
108.4,76.5,29.4,8.2.HRMS(ESI):exact mass calculated for M+(C32H25ClNO3)requires
m/z 506.1445,found m/z 506.1416.
Embodiment 7
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2g (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ag (80%).1H NMR(CDCl3,500MHz):δ(ppm)8.13(s,1H),7.89-7.87
(m,1H),7.69-7.67(m,1H),7.48-7.42(m,4H),7.39-7.27(m,7H),7.24-7.23(m,2H),6.80-
6.78 (m, 2H), 5.36 (s, 1H), 2.26 (q, J=10.0Hz, 2H), 0.87 (t, J=10.0Hz, 3H)13C NMR(CDCl3,
125MHz):δ(ppm)205.5,177.8,159.7,155.5,135.8,135.7,134.2,130.9,130.3,129.7,
128.6,128.6,128.5,128.4,127.9,127.8,127.7,127.6,126.5,122.9,115.5,113.7,
108.4,76.5,29.4,8.2.HRMS(ESI):exact mass calculated for M+(C32H25BrNO3)requires
m/z 550.0940,found m/z 550.0942.
Embodiment 8
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2h (0.06mmol, 12.2mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ah (90%).1H NMR(CDCl3,500MHz):δ(ppm)7.80-7.76(m,2H),7.49-
7.43(m,4H),7.38-7.27(m,9H),7.24-7.21(m,1H),6.79-6.77(m,2H),5.49(s,1H),2.39(s,
3H), 2.27 (q, J=10.0Hz, 2H), 0.87 (t, J=10.0Hz, 3H)13C NMR(CDCl3,125MHz):δ(ppm)
205.6,178.4,161.3,155.5,138.7,135.9,134.4,133.7,129.7,128.7,128.6,128.6,
128.5,128.4,127.8,127.7,125.5,125.2,115.5,113.6,108.6,76.3,29.5,21.2,8.2.HRMS
(ESI):exact mass calculated for M+(C33H28NO3)requires m/z 486.1991,found m/z
486.1990.
Embodiment 9
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2i (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ai (90%).1H NMR(CDCl3,500MHz):δ(ppm)7.65-7.64(m,1H),7.58-
7.56(m,2H),7.52-7.46(m,3H),7.41-7.27(m,10H),6.82-6.78(m,2H),6.51(s,1H),2.36
(q, J=10.0Hz, 2H), 1.01 (t, J=10.0Hz, 3H)13C NMR(CDCl3,125MHz):δ(ppm)205.4,178.0,
160.6,155.5,135.8,134.4,134.2,132.8,131.4,129.8,128.8,128.6,128.5,128.5,
127.9,127.8,127.8,127.3,121.8,115.5,113.7,110.0,108.4,76.6,29.2,8.3.HRMS
(ESI):exact mass calculated for M+(C32H25BrNO3)requires m/z 550.0940,found m/z
550.0949.
Embodiment 10
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1a (0.05mmol, 15.0mg), substrate
2j (0.06mmol, 15.1mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3aj (71%).1H NMR(CDCl3,500MHz):δ(ppm)7.74-7.72(m,2H),7.52-
7.48(m,4H),7.40-7.27(m,7H),7.25-7.20(m,3H),7.15-7.13(m,3H),6.87-6.82(m,4H),
6.20(s,1H),3.80(s,3H),3.58-3.51(m,2H).13C NMR(CDCl3,125MHz):δ(ppm)205.5,177.8,
163.0,160.4,155.3,135.9,134.5,134.1,130.5,129.7,128.7,128.6,128.5,128.4,
128.0,127.9,127.8,127.1,117.9,115.5,114.0,108.9,76.5,55.4,42.4.HRMS(ESI):
exact mass calculated for M+(C38H30NO4)requires m/z 564.2169,found m/z
564.2166.
Embodiment 11
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1b (0.05mmol, 16.7mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ba (85%).1H NMR(CDCl3,500MHz):δ(ppm)8.16(s,1H),7.91-7.90
(m,1H),7.70-7.68(m,1H),7.47-7.32(m,9H),7.29-7.27(m,2H),7.25-7.24(m,1H),6.81-
6.80 (m, 2H), 6.02 (s, 1H), 2.28 (q, J=10.0Hz, 2H), 0.90 (t, J=10.0Hz, 3H)13C NMR(CDCl3,
125MHz):δ(ppm)205.6,177.5,159.8,155.5,135.9,135.6,133.9,132.7,130.9,130.4,
130.0,129.7,128.6,128.6,128.5,127.9,127.5,126.5,122.9,115.6,114.1,107.5,76.3,
29.5,8.2.HRMS(ESI):exact mass calculated for M+(C32H24BrClNO3)requires m/z
587.0686,found m/z 587.0683.
Embodiment 12
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1c (0.05mmol, 18.9mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ca (75%).1H NMR(CDCl3,500MHz):δ(ppm)8.14(m,1H),7.90-7.88
(m,1H),7.70-7.69(m,1H),7.42-7.28(m,10H),7.24-7.22(m,2H),6.83-6.78(m,2H),2.23
(q, J=10.0Hz, 2H), 0.87 (t, J=10.0Hz, 3H)13C NMR(CDCl3,125MHz):δ(ppm)205.6,177.5,
159.8,155.5,135.9,135.5,133.3,131.6,130.9,130.4,130.3,129.7,128.6,128.5,
127.9,127.5,126.5,122.9,122.1,115.6,114.1,107.5,76.2,29.5,8.2.HRMS(ESI):exact
mass calculated for M+(C32H24Br2NO3)requires m/z 634.0415,found m/z 634.0416.
Embodiment 13
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1d (0.05mmol, 15.7mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3da (79%).1H NMR(CDCl3,500MHz):δ(ppm)8.17(s,1H),7.92-7.90
(m,1H),7.68-7.67(m,1H),7.47-7.45(m,2H),7.40-7.36(m,4H),7.34-7.27(m,4H),7.12-
7.11 (m, 2H), 6.82-6.80 (m, 2H), 6.28 (s, 1H), 2.33-2.29 (m, 5H), 0.90 (t, J=10.0Hz, 3H)13C
NMR(CDCl3,125MHz):δ(ppm)205.4,177.8,159.7,155.3,137.7,135.9,135.7,131.2,
130.9,130.3,129.7,129.1,128.5,128.5,128.5,127.9,127.7,127.7,126.5,122.9,
115.5,113.5,108.3,76.5,29.4,21.2,8.2.HRMS(ESI):exact mass calculated for M+
(C33H27BrNO3)requires m/z 564.1174,found m/z 564.1168.
Embodiment 14
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1e (0.05mmol, 16.5mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ea (82%).1H NMR(CDCl3,500MHz):δ(ppm)8.14(m,1H),7.90-7.88
(m,1H),7.69-7.67(m,1H),7.43-7.27(m,9H),7.25-7.24(m,1H),6.83-6.78(m,4H),5.58
(s, 1H), 3.76 (s, 3H), 2.26 (q, J=10.0Hz, 2H), 0.87 (t, J=5.0Hz, 3H)13C NMR(CDCl3,
125MHz):δ(ppm)205.4,177.8,159.7,159.2,155.4,136.0,135.7,130.9,130.3,129.9,
129.7,128.5,128.5,127.9,127.7,127.7,126.5,126.4,122.9,115.5,113.8,113.3,
108.0,76.6,55.2,29.3,8.2.HRMS(ESI):exact mass calculated for M+(C33H27BrNO4)
requires m/z 580.1123,found m/z 580.1120.
Embodiment 15
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1f (0.05mmol, 15.9mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3fa (77%).1H NMR(CDCl3,500MHz):δ(ppm)8.14(m,1H),7.91-7.89
(m,1H),7.70-7.69(m,1H),7.43-7.27(m,9H),7.24-7.22(m,2H),6.97-6.93(m,1H),6.79-
6.78 (m, 2H), 5.17 (s, 1H), 2.24 (q, J=10.0Hz, 2H), 0.87 (t, J=10.0Hz, 3H)13C NMR(CDCl3,
125MHz): δ (ppm) 205.6,177.4,162.5 (d, J=980.0Hz), 159.8,155.5,136.5,135.8,135.5,
(130.9,130.4,129.9 d, J=30.0Hz), 129.7,128.6,128.5,128.3,128.0,127.5 (d, J=
40.0Hz), 126.6,124.4,122.9,115.7 (d, J=90.0Hz), 115.6,114.8 (d, J=85.0Hz), 114.3,
107.5,76.3,29.5,8.2.HRMS(ESI):exact mass calculated for M+(C32H24BrFNO3)
requires m/z 568.0924,found m/z 568.0924.
Embodiment 16
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1g (0.05mmol, 18.9mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ga (74%).1H NMR(CDCl3,500MHz):δ(ppm)8.01(s,1H),7.87-7.86
(m,1H),7.54-7.51(m,3H),7.49-7.47(m,2H),7.42-7.38(m,3H),7.35-7.27(m,5H),6.83-
6.81 (m, 2H), 6.10 (s, 1H), 2.32 (q, J=10.0Hz, 2H), 0.92 (t, J=10.0Hz, 3H)13C NMR(CDCl3,
125MHz):δ(ppm)205.6,177.4,159.9,155.6,136.3,135.9,135.5,131.6,130.9,130.9,
130.4,129.9,129.7,128.6,128.6,128.0,127.3,126.6,122.9,122.3,115.6,114.3,
107.3,76.3,29.4,8.2.HRMS(ESI):exact mass calculated for M+(C32H24BrClNO3)
requires m/z 583.0550,found m/z 583.0547.
Embodiment 17
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1h (0.05mmol, 15.7mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ha (85%).1H NMR(CDCl3,500MHz):δ(ppm)8.14(m,1H),7.89-7.88
(m,1H),7.68-7.67(m,1H),7.45-7.43(m,2H),7.39-7.27(m,8H),7.19-7.16(m,1H),7.07-
7.05 (m, 1H), 6.81-6.79 (m, 2H), 5.86 (s, 1H), 2.28-2.26 (m, 5H), 0.88 (t, J=10.0Hz, 3H)13C
NMR(CDCl3,125MHz):δ(ppm)205.3,177.8,159.7,155.4,138.0,135.9,135.7,134.1,
130.9,130.3,129.7,129.3,128.7,128.6,128.5,128.3,127.8,127.7,127.7,126.5,
125.7,122.8,115.5,113.5,108.5,76.5,29.3,21.5,8.2.HRMS(ESI):exact mass
calculated for M+(C33H27BrNO3)requires m/z 564.1174,found m/z 564.1173.
Embodiment 18
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1i (0.05mmol, 18.9mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ia (86%).1H NMR(CDCl3,500MHz):δ(ppm)8.04(m,1H),7.83-7.81
(m,1H),7.66-7.65(m,1H),7.53-7.52(m,1H),7.44-7.41(m,3H),7.37-7.27(m,7H),7.13-
7.10 (m, 1H), 6.81-6.79 (m, 2H), 2.25 (q, J=10.0Hz, 2H), 0.84 (t, J=10.0Hz, 3H)13C NMR
(CDCl3,125MHz):δ(ppm)204.1,177.7,159.7,155.5,135.7,135.5,135.3,132.9,131.3,
130.9,130.3,130.1,129.4,129.0,128.3,127.8,127.6,127.4,127.1,126.5,124.9,
122.8,115.4,114.5,106.9,76.4,29.8,8.3.HRMS(ESI):exact mass calculated for M+
(C32H24Br2NO3)requires m/z 628.0045,found m/z 628.0042.
Embodiment 19
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1j (0.05mmol, 16.7mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ja (88%).1H NMR(CDCl3,500MHz):δ(ppm)8.20(s,1H),7.94-7.93
(m,1H),7.68-7.67(m,1H),7.57-7.55(m,2H),7.46-7.41(m,2H),7.38-7.29(m,8H),6.90-
6.86 (m, 2H), 2.35 (q, J=10.0Hz, 2H), 0.86 (t, J=10.0Hz, 3H)13C NMR(CDCl3,125MHz):δ
(ppm)205.4,177.6,159.8,155.7,135.8,134.4,133.9,133.7,130.9,130.3,129.8,129.6,
128.8,128.6,128.5,128.0,127.5,127.2,126.5,122.9,115.6,112.9,108.7,76.5,29.4,
8.2.HRMS(ESI):exact mass calculated for M+(C32H24BrClNO3)requires m/z 586.0608,
found m/z 586.0598.
Embodiment 20
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times.By substrate 1k (0.05mmol, 15.3mg), substrate
2a (0.06mmol, 16.0mg), CPA (0.0005mmol, 0.38mg) are successively weighed into reaction tube, and nitrogen is changed in evacuation, and in nitrogen
Methylene chloride (0.3mL) is added under atmosphere, reacts 36 hours at room temperature.TCL is detected after reaction, directly plus silica gel, rotation
Dry chromatography obtains yellow oil 3ka (91%).1H NMR(CDCl3,500MHz):δ(ppm)8.21-8.20(m,1H),7.97-
7.94(m,1H),7.70-7.69(m,1H),7.51-7.46(m,2H),7.41-7.27(m,5H),7.25-7.23(m,2H),
(7.19-7.18 m, 1H), 6.81-6.78 (m, 2H), 6.03 (s, 1H), 2.39-2.29 (m, 2H), 0.91 (t, J=10.0Hz,
3H).13C NMR(CDCl3,125MHz):δ(ppm)205.7,177.3,159.8,155.5,135.8,133.6,130.9,
130.4,129.9,129.7,128.6,128.5,128.4,128.2,127.8,127.6,126.6,125.3,122.9,
122.7,115.5,114.2,104.3,76.0,29.8,8.2.HRMS(ESI):exact mass calculated for M+
(C30H23BrNO3S)requires m/z 558.0562,found m/z 558.0555.
Claims (5)
1. the new methods that a kind of synthesis four replaces connection alkene, which is characterized in that with compound 1 be reaction raw materials, be with chiral phosphoric acid
Catalyst, reaction obtains four substitutions connection vinyl compound in reaction dissolvent under certain temperature；Wherein, the temperature is 0-80
℃；Shown in reaction process such as formula (I)；
Wherein R1, R2, R3And R4It is alkyl, aromatic radical or heterocycle.
2. as described in claim 1 four replace the synthetic method of connection vinyl compound, which is characterized in that the catalyst is hand
Property phosphoric acid；The dosage of the catalyst is 1-100%.
3. as described in claim 1 four replace the synthetic method of connection vinyl compound, which is characterized in that the reaction dissolvent is
Methylene chloride, chloroform, tetrahydrofuran, methanol, 1,2- dichloroethanes, acetonitrile, toluene, 1,4- dioxane, ether, acetic acid
Ethyl ester, benzotrifluoride, xylene compound or methyl phenyl ethers anisole.
4. as described in claim 1 four replace the synthetic method of connection vinyl compound, which is characterized in that 1 He of compound
The ratio of compound 2 is 1:1-1:5.
5. one kind four replaces the synthetic method of connection vinyl compound, reaction process is as shown in following formulas；
In the test tube reactor of 25mL, with nitrogen exchange of air 3 times；By 0.05 mmol substrate 1a, 0.06 mmol substrate 2a
It is successively weighed into reaction tube with 0.0005 mmol CPA, nitrogen is changed in evacuation, and 0.3 mL methylene chloride is added under nitrogen atmosphere；
Reaction system is reacted at room temperature 36 hours；TCL is detected after reaction, and directly plus silica gel, rotation dry chromatography obtain 3aa.
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| CN111704586A (en) * | 2020-07-08 | 2020-09-25 | 青岛大学 | Novel method for synthesizing chiral tetra-substituted allene compound |
| CN114133384A (en) * | 2021-12-08 | 2022-03-04 | 深圳市众康动保科技有限公司 | Preparation method of chiral isoxazolone compound |
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